Abstract 4300: AT1965, a novel mRNA cap 2′O methylation inhibitor, exerts potent antitumor activity and enhances chemotherapy efficacy

Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2′-O positions of the 5′ guanosine cap by specific nuclear and cytoplasmic methyltransferases. N-7 methylation is essential for RNA translation and stability. Recent studies have highlighted the critical role of 2′O methylation of the cap in enabling the innate immune system to distinguish self-RNA from foreign RNA through pattern recognition receptors, such as RIG-I. Despite advances in understanding RNA modifications, the therapeutic potential of targeting RNA capping enzymes remains unexplored. Here, we report that AT1965, a novel mRNA cap 2′O methylation inhibitor, exhibits potent antitumor effects and significant synergy with cabazitaxel, an FDA-approved anticancer agent. Subcutaneous Lewis Lung Carcinoma (LLC) tumors were established in C57BL/6 mice, divided into three groups: untreated controls, those treated with cabazitaxel alone, and those treated with cabazitaxel in combination with AT1965. The combination therapy resulted in a mean tumor size reduction of 23.6%, while tumors in the other groups increased in size. Mechanistically, AT1965 impairs mRNA stability and translation of key oncogenic transcripts, sensitizing tumors to cytotoxic agents. These findings underscore the potential of RNA capping enzymes as therapeutic targets in cancer. Future studies should explore the application of AT1965 in other tumor models and its potential to synergize with diverse chemotherapeutics. Citation Format: Arshit Narang, Vinay S. Mahajan, Shiladitya Sengupta. AT1965, a novel mRNA cap 2′O methylation inhibitor, exerts potent antitumor activity and enhances chemotherapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4300.